Submissions for variant NM_014908.4(DOLK):c.1450A>G (p.Ile484Val)

gnomAD frequency: 0.00044  dbSNP: rs147630977

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213916	SCV000269035	benign	not specified	2015-03-11	criteria provided, single submitter	clinical testing	p.Ile484Val in exon 1 of DOLK: This variant is not expected to have clinical sig nificance it has been identified in 1.1% (183/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs147630977).
GeneDx	RCV000213916	SCV000528927	benign	not specified	2016-11-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000549094	SCV000638509	benign	DK1-congenital disorder of glycosylation	2024-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000549094	SCV001329958	likely benign	DK1-congenital disorder of glycosylation	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV002390568	SCV002696859	likely benign	Cardiovascular phenotype	2019-01-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV003430772	SCV004156445	benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	DOLK: BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213916	SCV004223822	likely benign	not specified	2023-11-14	criteria provided, single submitter	clinical testing	Variant summary: DOLK c.1450A>G (p.Ile484Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251468 control chromosomes, predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8.94 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOLK causing DK1-Congenital Disorder Of Glycosylation phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1450A>G has been reported in the literature in an individual affected with L Carnitine deficiency, speaking delay, elevated pyruvic acid and ethylmalonic acid without strong evidence of causality (Jalkh_2019). This report does not provide unequivocal conclusions about association of the variant with DK1-Congenital Disorder Of Glycosylation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30665423). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.